title: A role for interleukin-17A in modulating intracellular survival of Mycobacterium bovis bacillus Calmette-Guérin in murine macrophages.
abstract: Interleukin 17A IL-17A is a crucial immunomodulator in various chronic immunological diseases including rheumatoid arthritis and inflammatory bowel disease. The cytokine has also been demonstrated to control the pathogenesis of the Mycobacterium tuberculosis by dysregulating production of cytokines and chemokines and promoting granuloma formation. Whether IL-17A regulates innate defence mechanisms of macrophages in response to mycobacterial infection remains to be elucidated. In the current report, we investigated the effects of IL-17A on modulating the intracellular survival of Mycobacterium bovis bacillus Calmette-Guérin (BCG) in RAW264.7 murine macrophages. We observed that IL-17A pre-treatment for 24 hr was able to synergistically enhance BCG-induced nitric oxide (NO) production and inducible nitric oxide synthase expression in dose- and time-dependent manners. We further delineated the mechanisms involved in this synergistic reaction. IL-17A was found to specifically enhanced BCG-induced phosphorylation of Jun N-terminal kinase (JNK), but not of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase. By using a specific JNK inhibitor (SP600125), we found that the production of NO in BCG-infected macrophages was significantly suppressed. Taken together, we confirmed the involvement of the JNK pathway in IL-17A-enhanced NO production in BCG-infected macrophages. We further demonstrated that IL-17A significantly enhanced the clearance of intracellular BCG by macrophages through an NO-dependent killing mechanism. In conclusion, our study revealed an anti-mycobacterial role of IL-17A through priming the macrophages to produce NO in response to mycobacterial infection.
authors.affiliation: Cytokine Biology Group, Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
authors.forename: Wai Lim
authors.initials: WL
authors.lastname: Ling
authors.forename: Liang Jie
authors.initials: LJ
authors.lastname: Wang
authors.forename: John C H
authors.initials: JC
authors.lastname: Pong
authors.forename: Allan S Y
authors.initials: AS
authors.lastname: Lau
authors.forename: James C B
authors.initials: JC
authors.lastname: Li
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D058491:Bacterial Load / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D006801:Humans; D020381:Interleukin-17 / Q000494:pharmacology / Q000502:physiology*; D042541:Intracellular Space / Q000187:drug effects / Q000276:immunology; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology*; D051379:Mice; D009163:Mycobacterium bovis / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation; D014376:Tuberculosis / Q000276:immunology*
chemical_list: D000873:Anthracenes; D020381:Interleukin-17; C432165:pyrazolanthrone; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D048670:MAP Kinase Kinase 4
keywords: innate immunity; nitric oxide; tuberculosis